Seminar Shayana

8/8/2019 Seminar Shayana

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Polymorphism Powder FlowSurface Properties

Presented By:-

Shayana Gora M.Pharm Quality Assurance1st Semester



What is PolymorphismWhat is Polymorphism??

Habit

Single Entity

Polymorphs

Channel Layer Cage

(Clathrate)

NonstoichiometricInclusion Compound

StoichiometricSolvates (Hydrates)

Molecular Adducts

Crystalline Amorphous

Internal Structure

Chemical Compound

Ordered

arrangement

Disordered

arrangement

ICH Definitionon Polymorphism



POLYMORPHISMPOLYMORPHISMMany drug substance can exist in more than

one crystalline form with different space lattice

arrangements.

Classified into two form-

1.Enantiotropic e.g. Sulfur

2.Monotropic e.g. glyceryl stearate

Polymorphic solids have different unit cells.In general, the stable polymorph exhibits the

highest melting point , the lowest solubility, andthe maximum chemical stability.



It is important to identify the polymorph that is stable atroom temperature.

To determine whether the polymorpic transition arepossible within the temp. range used for stability

studies & during processing(drying,milling).

The particular polymorph formed by a drug depends

on the

conditions of crystallisation; for example, the solventused,

the rate of crystallisation and the temperature.



Pharm. Properties Exhibited Pharm. Properties Exhibited

by Different Polymorphs by Different PolymorphsMelting Point

Hygroscopicity

Chemical and Physical Stability

Apparent Solubility and Dissolution

Bioavailability and Bioequivalence

Manufacturability



When some compounds crystallise they may

entrap solvent in the crystal. Crystals thatcontain solvent of crystallisation are called

crystal solvates, or crystal hydrates when

water is the solvent of crystallisation. Crystals that contain no water of crystallisation

are termed anhydrates.

There are two main types of crystal solvate:1 . Polymorphic solvates

2. Pseudopolymorphic solvates



The particular solvate formed by a drug depends on theconditions of crystallisation, particularly the solvent used.

The solvated forms of a drug have different physicochemicalproperties to the anhydrous form:

The melting point of the anhydrous crystal is usually higher

than that of the hydrate.

Anhydrous crystals usually have higher aqueous solubilitiesthan hydrates.

The rates of dissolution of various solvated forms of a drug

differ but are generally higher than that of the anhydrous form.

There may be measurable differences in bioavailabilities of the

solvates of a particular drug; for example, the monoethanol

solvate of prednisolone tertiary butyl acetate has an absorption

rate in vivo which is nearly five times greater than that of the

anhydrous form of this drug.



Clathrates or inclusion compounds:- Achemical substance consisting of a lattice of

one type of crystal structure trapping and

containing a second type of molecule.Therefore, a clathrate is a material which is a

weak composite, in which molecules of suitable

size are captured in spaces in the crystal lattice.

Molecules of one substance are completely

enclosed within the crystal structure of another.



F

ormulation problems Polymorphs with certain crystal habits may be

difficult to inject in suspension form or to

formulate as tablets.

Transformation between polymorphic forms

during storage can cause changes in crystal

size in suspensions and their eventual caking.

Crystal growth in creams as a result of phasetransformation can cause the cream to become

gritty.



Changes in polymorphic forms of vehicles such

as theobroma oil, used to make suppositories,could cause products with different and

unacceptable melting characteristics

A nalytical issues Difficulties in identification arise when samples

that are thought to be the same substance givedifferent infrared spectra in the solid state

because they exist in different polymorphic

forms



.

Change in polymorphic form can be caused by

grinding with potassium bromide when samplesare being prepared for infrared analysis.

Changes in crystal form can also be induced bysolvent extraction methods used for isolation of

drugs from formulations prior to examination by

infrared spectroscopy ± these can be avoided

by converting both samples and reference

material into the same form by recrystallisation

from the same solvent.



BIOAVAILABILITY DIFFERENCES The difference in the bioavailability of different

polymorphic forms of a drug is usually

insignificant but is a problem in the case of thechloramphenicol palmitate, one (form A) of the

three polymorphic forms of which is poorly

absorbed.



High M.P. Strong lattice hard to

remove a molecule Low Dissolution rate

Amorphous > metastable > crystalline

order of dissolution rate

Since the metastable forms have higher

aqueous stability, they show better bioavailability therefore they are preffered in

formulation



TECHNIQUES FOR STUDIES OF

CRYSTALS

MICROSCOPY

HOT STAGE MICROSCOPY

THERMAL ANALYSIS

X-RAY DIFFRACTION



MI CROSCO PY

Materials with more than one refractive indexare anisotropic and appear bright with brilliant

colours against black polarised background.

The color intensity depends upon crystal

thickness.

Isotropic material have single refractive index

and this substance do not transmit light with

crossed polarising filter and appears black.



A dvantage

By this method, we can study crystalmorphology and difference between

polymorphic form.

DisadvantageThis require a well trained optical

crystallographer,as there are many possiblecrystal habit and their appearance at different

orientation.



Hot Stage Microscopy

The polishing microscope fitted with hot stage is

useful for investigating polymorphism, melting

point and transition temperature.

Disadvantage

In this technique, the organic molecule candegrade during the melting process and

recrystallization of the melt may not occur.



TH E RMAL ANALYSI S

Differential Scanning Calorimetry (DSC) andDifferential Thermal Analysis (DTA) are

particularly useful in the investigation of

polymorphism.It measures the heat loss/gain resulting from

physical/chemical changes within a sample as a

function of temperature.

For characterising crysatl forms, the heat of

fusion can be obtained from the area under

DSC for melting endotherms.



Similarly, heat of transition from one polymorph

to another may be calculated. A sharp symmetric melting endotherm can

indicate relative purity of molecule.

A broad asymmetric indicates presence of impurities.

Disadvantage

Degradation during thermal analysis may

provide misleading results.



X ² R A Y diffraction

Working:- When beam of non homogenous X-ray is allowed to pass through the crystal, X-ray

beam is diffracted and it is recorded by means

of photographic plate.Diffraction is due to crystal which acts as 3D

diffraction grating toward X-ray.

Random orientation of crystal lattice in thepowder causes the X-ray to scatter in a

reproducible pattern of peak intensities.



Mixtures of different crystalline forms can beanalyzed using normalized intensities at

specific angles, which are unique for each

crysatlline form.

An amorphous form doesnot produce a pattern.

Single- crystal X-ray provide the most complete

information about the solid dtate.



Powd er F low Powd er F low



When we are concerned with the flow of any material it relates

with Rheology.

Powders are classified into

1. Free flowing

2. NON free flowing(cohesive powder)

If not of proper density then are densified by SLUGGING

Fundamental properties:- properties that relates to the

individual particle . Derived properties:- They are dependant on fundamental

properties & well defines the basic factors relating tomeasurements.



Good flow properties are a prerequisite for the successfulmanufacture of both tablets and powder-filled hard gelatin

capsules.

It is a property of all powders to resist the differential movementbetween particles when subjected to external stresses.

This resistance is due to the cohesive forces between particles.

Three principal types of interparticle forces have beenidentified:-

forces due to electrostatic charging

vander Waals forces

forces due to moisture



Powders with particles below 50 µm will

generally exhibit irregular or no flow due

to vander Waals forces.

Particle shape is also important; for

example, the force between a sphereand plane surface is about twice that

between two equal sized spheres.



Nature of particle Effect on flow property

Smooth surface Increase the flow property

Rough surface Poor flow due to friction

Flat and elongated particle Gives high porosity

high density & low porosity Good flow property



volumes Definitions

True volume Volume of powder itself

Granule volume Volume of powder + voids (inter

particle spaces)

Bulk volume Volume of powder + volume of intra

particle space+ voids

Void volume Bulk volume ± true volume (Vb - Vp)



POROSITY ( ) or V OIDS :- It is the space between the particle.

It is the ratio of void volume to the bulk volume of the packing.

Where ,

Vp = true volume

Vb = bulk volume

V = void volume

= (Vb-Vp)/Vb

= 1- (Vp/Vb)

% porosity = 100



Theoretical porosity of powder consist of

uniform sphere inClosest packing- 26%

Loosest packing- 48%

Real powder have porosity in between 30 to50%.

In suspension, porosity may be above the

theoretical max limit 48%.Crystalline materials porosity- <1% (under force

10000 lb/in2)



T hree types of densities DEN SI T Y - Universally defined as weight per unit volume.

1. True d ensity:- it is the weight of material itself

2.G ranule d en sity:-

Measured by mercury displacement method.

Mercury fills the voids, but fails to penetrate internal particlesas it has non weighting properties.

Granule volume related to weight of the mercury that displaced

by granules in pycnometer.

Granule density = granule weight

granule volume



BULK DENSITY:-

Bulk density = mass of the powder (w)

bulk vol ume (Vb)

When particle are loosely packed ,there arelots of gaps in between particles, bulk volumeincreases making powder light.

Powder classified as light¶or heavy¶³ ´

34



Minimum bulk density is when the volume of thepowder is at a maximum, caused by aeration, just prior to completebreakup of the bulk.

Poured bulk density is when the volume ismeasured after pouring powder into a cylinder,creating a relatively loosestructure.

Tapped bulk density is, in theory, themaximum bulk density that can be achieved

without deformation of the particles.



Changes in Bulk Density: Changes in Bulk Density:

Ratios of the poured to tapped bulk

densities are expressed in two ways togive indices of flowability.

1.Hausner Ratio2.Carr¶s compressibility index



Hausner Ratio = tapped density

bulk density

The Hausner Ratio varies from about 1.2 for a free-flowing powder to 1.6 for cohesive powder

less than 1.25 (equivalent to 20% carrs) indicatesgood flow.

Greater than 1.5(equivalent to 33% carrs)indicatespoor flow.

Between 1.25 & 1.5- added glidant ± improves flow



A ng le o f R epo se A ng le o f R epo se

Maximum angle possible between the surfaceof a pile of powder and the horizontal plane.

It is a function of the surface roughness.

The angle of repose is determined by allowing amass of powder to flow freely through an orificefrom a height and form a conical heap on thehorizontal surface.

As the heap is formed, the particles slip and rollover each other until the mutual frictionbetween the partcles just balance thegravitational force.



By definition,

tan = h/r

= tan-1

(h/r)

where, h = height of pile

r =radius of base of the pile

=angle of repose



Relationship between flow, angle of

repose, Carr¶s index .

Flow Angle of repose Carr¶s index

( % )

Excellent <25 5-15

Good 25-30 12-16

Fair topassable

30-40 18-21

Poor > 40 23-35

Very Poor 33-38

Extremely Poor >40



EFFECT ON ANGLE OF REPOSE OF VARIOUS

PROCEDURE

decrease particle size- higher angle of repose

Fines (up to 15%)-increase angle of repose

Lubricants at low concentration- angle of repose

Rough & irregular surface- higher angle of repose

Lower the angle of repose- better the flow property



Higher the moisture content greater the cohesion &

adhesion.

Flow properties can be improved by following

methods-

1. Altering the particle size

2. Removal or Addition of Fines ( upto 15% )

3. Altering the particle shape and texture

4. Altering the surface forces

5. Removing extra moisture

6. Adding flow activators or Glidants



Surf

aceProp

erti es



When two phases are in contact with each other, the

boundary between them is referred to as interface.

If one of the two phases is a gas or vapor, the term

surface is generally used instead of interface.

Molecules at the surface do not have their attraction

forces properly balanced. They experience an inwardforce of attraction towards the bulk of the liquid. The

surface of a liquid therefore gets contracted and

molecules at the interface are pulled together. The

force which has to be applied to counterbalanceexactly this inward pull is known as the surface

tension.

Interfacial tension is the force acting between two

immiscible liquid phases.



ADHESIONAL FORCES

1. Forces which act

between molecules of

different phases.

2. Tend to increase the

affinity of two phases.

COHESIONAL FORCES

1. Forces which act

between molecules of

the same phase.

2. Tend to keep the

phases separate.



MEASUREMENT OF SURFACE AND

INTERFACIAL TENSION

I. Capillary Rise Method

II. Drop Weight and Drop Count Methods

III. Wilhelmy Plate Method

IV. Ring Detachment Method ( Du NouyTensiometer)

If ll tit f i i ibl li id i l d



If small quantity of an immiscible liquid is placed on

the surface of another liquid, it will either spread as a

film on the surface of the other liquid or remain as a

drop or lens.

Which of the two applies generally depends on the

achievement of a state of minimum free energy.

The ability of one liquid to spread over another can be

assessed in terms of spreading coefficient whose

value should either be positive or zero for spreading tooccur.

The spreading coefficient is the difference between

the



work of adhesion and the work of cohesion.(Wa-Wc).

This implies that if work of adhesion is morethan the work of cohesion, spreading will occur.

where gw is the sublayer liquid surface

tension, go is the spreading liquid surfacetension and ow is the interfacial tensionbetween the two layers

S f t t d th t l th f



Surfactants are compounds that lower the surface

tension of a liquid, allowing easier spreading, and

lowering of the interfacial tension between two

liquids, or between a liquid and a solid.

T CLASSIFICATION

a) A nionic surfactants:- alkali soaps, amine soaps b) Cationic surfactants:- quaternary ammonium

compounds such as cetrimide, benzalkonium

chloride

c) A mpholytic surfactants:- lecithind ) N onionic surfactants:- glycerl monostearate,

macrogol esters, tween,span

HLB SYSTEM



HL B SYSTEM

1. Surfactant possess both hydrophilic and lipophilicportions, so there must be some scale to measure the

balance between these two opposing tendencies.

2. Griffin (1949) developed an arbitrary scale to serveas a measure of hydrophilic-lipophilic balance (HLB) of

surface active agents.

3. This HLB scale is numerical scale extending from 1to 20.

4. The more hydrophilic surfactants have a high HLBnumber > 10, while surfactants with an HLB < 10 areconsidered to be lipophilic.

5. The HLB value helps in the selection of a proper



surfactant for a particular application.

6. The HLB of a number of polyhydric alcohols and

fatty acid esters such as glyceryl monostearate, canbe calculated by using the formula:

HLB = 20(1 - S/A)

saponification number for many substances like bees-wax and wool-fat derivatives where S is thesaponification number of the ester and A is the acidnumber of the fatty acid.

7. . But the saponification number for manysubstances like bees-wax and wool-fat derivativescannot be easily estimated.



11 The summation of the respective group number



11. The summation of the respective group number permits the calculation of the HLB value according tothe equation

HLB = (hydrophilic group numbers) - (lipophilicgroup numbers) + 7

HL B VALUES AND THEIR APPLICATIONS A value from 0 to 3 indicates an anti-foaming agent

A value from 4 to 6 indicates a W/O emulsifier

A value from 7 to 9 indicates a wetting agent

A value from 8 to 18 indicates an O/W emulsifier A value from 13 to 15 is typical of detergents

A value of 10 to 18 indicates a solubiliser or hydrotrope



T W ETTING is the ability of a liquid to maintaincontact with a solid surface, resulting fromintermolecular interactions when the two arebrought together.

The degree of wetting (wettability) isdetermined by a force balance betweenadhesive and cohesive forces.

Wetting and the surface forces that controlwetting are also responsible for other relatedeffects, including so-called capillary effects.



DETERGENCY

Ability of a detergent to lift soil (dirt and grease)

from a surface by displacing it with chemicals

(called surfactants) which adhere more readilyto the surface being cleaned than to the soil.

Detergent functions in the cleaning process Removal of the soil from the substrate

Prevention of its redeposition

ELECTRICAL PROPERTIES OF



ELECTRICAL PROPERTIES OF

INTERFACES

Electrical Double Layer

A double layer (DL, also called an electrical

double layer , EDL) is a structure that appearson the surface of an object when it is placed

into a liquid.

The object might be a solid particle, a gasbubble, a liquid droplet, or a porous body.

The DL refers to two parallel layers of charge

surrounding the object.

The first layer the surface charge (either



The first layer, the surface charge (either

positive or negative), comprises

ions adsorbed directly onto the object due to a

host of chemical interactions.

The second layer is composed of ions attracted

to the surface charge via the coulomb force,

electrically screening the first layer.

This second layer is loosely associated with the

object, because is made of free ions which

move in the fluid under the influence of electric

attraction and thermal motion rather than

being firmly anchored It is thus called the diffuse



being firmly anchored. It is thus called the diffuse

layer.

NER NST and ZE TA potential

The difference in electric potential between the actual

surface of the particle and the electroneutral region is

referred to as Nernst potential. Thus, Nernst potential is controlled by the electrical

potential at the surface of the particle due to the

potential determining ions.

the potential difference between the ions in the tightlybound layer and the electroneutral region, referred to

as zeta potential.



Zeta potential governs the degree of repulsion

between adjacent, similar charged, soliddispersed particles.

If the zeta potential is reduced below a critical

value (which depends on the particular system

being used) the force of attraction between

particles supersede the force of repulsion, and

the particles come together.

This phenomenon is referred to as flocculationand the loosely packed particles are called

floccule.



References

Ansel·s Pharmaceutical Dosage Forms and Drug Delivery Systems,Loyd V.Allen,Jr.,Nicholas G. Popovich,8th edition

Fast Track Physical Pharmacy, David Attwood, Alexander T. Florence, RPS Publishing

Martin·s Physical Pharmacy and Pharmaceutical Sciences,Alfred N. Martin,Lippincott Williams and Wilkins

A Textbook of Biopharmaceutics and Pharmacokinetics,

Dr.Javed Ali, Dr. R.K. Khar, Dr. Alka Ahuja, Birla Publications PVT. Limited

Pharmaceutical preformulation- The physiochemical properties of drug substance, James I. Wells

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